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Histone and DNA methyltransferases in optic nerve regeneration

视神经再生中的组蛋白和 DNA 甲基转移酶

基本信息

批准号：
10612888
负责人：
Dong Feng Chen
金额：
$ 29.55万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10612888
关键词：
Adopted Adult Affect Aging Axon Blindness Cell Aging Cell Separation Cell Survival Central Nervous System Chromatin Cre-LoxP DNA DNA Modification Methylases DNMT3a Deposition Development Disease Disease Progression Enhancers Epigenetic Process Event Eye diseases Failure Functional disorder Gene Expression Genes Glaucoma Growth Histones Homologous Gene In Vitro Injury Knock-out Knockout Mice Knowledge Laboratories Link Mammals Methylation Methyltransferase Microspheres Modeling Modification Molecular Mus Natural regeneration Nerve Nerve Crush Nerve Regeneration Nervous System Trauma Neurites Neurodegenerative Disorders Neurons Optic Nerve Optic Nerve Injuries Patients Persons Pilot Projects Regenerative capacity Research Retina Retinal Diseases Retinal Ganglion Cells Role System Testing Transposase Vision Work age related axon growth cell growth clinically relevant epigenomics histone methyltransferase in vivo in vivo regeneration injury recovery loss of function member methyl group nerve damage nerve repair neural neural growth neurite growth novel therapeutic intervention optic nerve disorder optic nerve regeneration postnatal programs regenerative retinal ganglion cell degeneration retinogenesis sight restoration small molecule stem cells transcriptome sequencing transcriptomics

项目摘要

Project summary Mature neurons in the central nervous system of adult mammals, including retinal ganglion cells (RGCs) whose axons form the optic nerve, are incapable of regenerating. This presents a major challenge to restoring vision in patients with optic nerve injury or diseases, such as glaucoma, an optic nerve disease that affects 80 million people globally. Long-standing works from my laboratory demonstrate that optic nerve elongation is a programed event during development whose shut-down contributes critically to the failure of optic nerve regeneration. Potentially, epigenetic modification may reprogram neurons to regain this capacity by reactivating progenitor cell genes that have been silenced during neural maturation. Methylation, a key epigenetic mechanism carried out by histone methyltransferases (HMTs) and DNA methyltransferases (DNMTs), is essential in retinogenesis. Increased levels of methylation and methyltransferases activity is highly correlated with aging and retinal diseases progression. However, the functional role of epigenetic factors HMTs and DNMTs in RGC degeneration, or glaucoma in general, is unclear. By examining specific epigenetic changes associated with RGCs in mouse, we recently detected dynamic expression of a major HMT, enhancer of zeste homolog 1 (Ezh1) and a key member of DNMTs, that inversely correlate with retinal neuritogenesis and the optic nerve regenerative capacity of RGCs. Importantly, our pilot study found that pan inhibition of Ezh1 or DNMTs by small-molecule compounds increased neurite outgrowth in primary RGCs in vitro, and mice carrying selective DNMT deficiency in RGCs promoted robust axon re-growth in vitro and in injured optic nerve in vivo. We hypothesized that resetting the developmental epigenetic program induced by Ezh1 or DNMTs promotes the regenerative capacity of the optic nerve. The hypothesis will be tested in two specific aims: (1) Exploit the molecular events by which Ezh1 and DNMTs regulate RGC neurite growth in vitro, and (2) Examine the role of Ezh1 or DNMTs in optic nerve growth in vivo. This study will advance our knowledge about the epigenetic modulation of neuritogenesis, with the potential of discovering novel therapeutic strategies against neurodegenerative diseases.

项目总结